ATBECHDE....FRGB..IT..LUNLSE......................MDIM360 - Ver 2.5 (21 Aug 1997) 2100000/0The file contains technical information submitted after the application was filed and not included in this specification0008802EUROPEAN PATENT SPECIFICATIONB119820721EP79103357.419790907enenen360807819780908GB198207211982291980031919800619820721198229198110083 3C 07D 457/02 A 3A 61K 31/48 BdeErgolinderivate, ihre Herstellung und diese enthaltende therapeutische ZusammensetzungenErgoline derivatives, their preparation and therapeutic composition containing themfrDérivés d'ergoline, leur préparation et composition thérapeutique les contenantFARMITALIA CARLO ERBA S.p.A.0024005032 296 a/kiCARLO ERBA S.p.A., FARMITALIAERBA S.p.A., FARMITALIA CARLOVia Carlo Imbonati, 24I-20159 MilanoITMantegani, SergioVia Carlo Pisacane 57I-MilanITArcari, Giuliana, Dr. Biolog.Via Sismondi 4I-MilanITCaravaggi, Anna MariaVia Conca del Naviglio 22I-MilanITBosisio, Germano Via De Santis, 23/BPalazzolo Milanese (Paderno Dugnano)I-MilanITEitle, Werner, Dipl.-Ing.et al00003344Hoffmann Eitle, Patent- und Rechtsanwälte, Postfach 81 04 2081904 MünchenDEATBECHDEFRGBITLUNLSE19800319198006

The invention relates to ergot derivatives, a process of preparing same and therapeutic composition.

Ergoline derivatives are described in CH-A-580 625, CH-A-605 936, DE―A1―2 803 255, GB-A-1 513 322, DE―A1―2 365 974 and CH-A-580 626. The known ergoline derivatives have good a-adrenolytic activity and an activity in inhibiting platelet aggregation. Some of them show a dopamine receptor stimulating activity. Nothing is reported in the prior art with respect to an anti-hypertensive activity.

Surpri ingly it has been found that the new ergoline derivates according to the invention show an antihypertensive activity and moderate to good anti-prolactinic activity.

The ergoline derivates according to the invention are of the general formula I: wherein R1 represents an alkyl or alkoxy group having from 1 to 4 carbon atoms, phenyl, a 5- or 6- membered heterocyclic ring which is preferably saturated, an amino group, a substituted amino group of the formula NHR' (wherein R' represents an alkyl group having from 1 to 4 carbon atoms, a cycloalkyl group, a benzyl group or a phenyl group), or a substituted amino group of the formula NR"R'" (wherein R" and R"' both represent alkyl groups having from 1 to 4 carbon atoms);

and the pharmaceutically acceptable addition salts with organic or inorganic acids thereof.

According to the embodiment of the invention wherein R, is alkyl, this is preferably the methyl group. When R, is a 5- or 6-membered heterocycle, this can advantageously be the piperidino, 1-pyrrolidinyl, morpholino or the 4-methyl-1-piperazinyl group.

Ergoline derivatives of the general formula I as above defined may be prepared by condensing a compound of the general formula II below with an alkaline salt of a compound of the general formula III below.

In the general formulae II and III R,, R2, R3, R4, Rs, R6 and R7 have the meanings given above. The condensation, which is a process within the scope of the invention, may be carried out in a polar aprotic solvent, suitable temperatures are in the range from 50 to 100°C and the reaction is usually terminated after 2 to 10 hours. Suitable polar aprotic solvents are dimethylsuifoxide, dimethylformamide and the like. The condensation is preferably carried out in the presence of sodium or potassium iodide. The condensation products may be purified by conventional procedures. Chromatography over silicagel is especially suitable.

Compounds according to the invention are useful as antihypertensive agents and also have moderate to good antiprolactinic activity. They can be used as an active ingredient in a therapeutical composition along with usual pharmaceutically acceptable additives.

Evaluation of anti-hypertensive activity 1. Spontaneously hypertensive rat (MHS)

Four spontaneously hypertensive male rats strain MHS weighing 250-300 g for each group were used. Animals were treated for four consecutive days. Drugs were administered by gastric gavage, suspended in 5% arabic gum (0,2 ml/100 g body weight) and blood pressure (BP) and heart rate (HR) were measured at the tail by BP Recorder W + W. Blood pressure and heart rate were measured on the first and fourth day of treatment 1 hour before and 1 and 5 hours after drug administration.

Results are reported in tables 1 and 2.

2. Normotensive rat (NR)

Blood pressure recordings have been made in conscious normotensive unrestrained rats weighing approximately 300 g, via a catheter chronically inserted into the left common carotid artery. Implantation of arterial cannula was made under sodium pentobarbital anaesthesia (50 mg/kg i.p.). A 1 cm long incision was made through the previously shaved ventral surface of the neck and the tissues overlying the trachea parted by blunt dissection to reveal the carotid artery. The polyethylene catheter used was made with PE 50 tubing, previously filled with saline containing 250 I.U./ml heparin. The tip of the cannula was pushed at least 2 cm inside the vessel toward the heart. The cannula was then firmly tied and passed beneath the skin to emerge from a small incision in the back of the neck. During the postoperative period and before the start of each recording session, the cannula was flushed through daily with saline containing heparin (250 i.U./m)). The experiments were performed two days after surgery. Drugs were administered by gastric gavage. Results are reported in Tables 3 and 4.

Evaluation of the toxicity (LD50)

Ten male mice for each group were orally treated with drugs at different dose levels for the determination of lethal dose 50 (LD50). Mice were observed for seven days after administration. LD50's are summarized in Table 5.

From the data reported in table 1 it is apparent that compounds according to the invention induce a consistent blood pressure fall in spontaneously hypertensive rats both at 2 and 5 mg/kg os. This reduction of the blood pressure appears not only on the first day of treatment but also on the fourth day showing absence of tachyphylaxis. Moreover the reduction lasts 5 hours at least. When compared with hydralazine and a-methyl-DOPA, two known antihypertensive drugs, the new compounds, at the 2 mg/kg level, are more active than hydralazine and more than 15 fold as active as a-methyl-DOPA. At 5 mg/kg level the new compounds are more active than hydralazine, particularly on the fourth day, and more than 20 fold as active as a-methyl-DOPA. When the variation of the heart rate (HR) is considered, it can be seen (table 2) that the new compounds induce only minor variations whereas α-methyl-DOPA greatly increases it, particularly at the 5 mg/kg level.

The results obtained in the incannulated normotensive rat (table 3) confirm the antihypertensive activity of the new compounds which compares favourably with that of hydralazine. Moreover the variations of the heart rate (table 4) are limited and in any case a favourable reduction rather than an unfavourable increase in the heart rate is observed. Finally the toxicity of the new compounds, expressed as LD50 (table 5), is no greater than that of hydralazine, being in many cases largely inferior and when the therapeutic ratio (activity versus toxicity) is considered, the new compounds result also largely better antihypertensive agents than α-methyl-DOPA.

Example 1 2-Cyano-3-(6'-methylergoline-8'β)-propionic acid ethyl ester

(I: R1 = OCH2CH3, R3 = CN, R4 = CH3, R2 = R5 = Re = R7 = H)

A mixture of 16.9 g of sodium ethyl cyanoacetate, 41 g of 6-methyl-8β-tosyloxymethylergoline and 16 g of potassium iodide in 250 ml of dimethylsulfoxide and 50 ml of ethyl cyanoacetate was heated under stirring at 70°C for 5 hours. The solution was poured into 7 litres of iced water, and the resultant precipitate was filtered off, dried and chromatographed on a silicagel column, using chloroform as eluent, to give 24 g of the title compound, m. p. 200-202°C.

Example 2 2-Cyano-3-(6'-methylergoline-8'β)-N-propionylmorpholine

(I: R1 = morpholino, R3 = CN, R4 = CH3, R2 = R5 = R6 = R7 = H)

A mixture of 0.85 g of sodium cyanoacetylmorpholine, 2 g of 6-methyl-8β-tosyloxymethyler- goline, 0.6 g of sodium iodide in 10 ml of dimethylsulfoxide and 2 g of cyanoacetylmorpholine was heated under stirring at 80°C for 10 hours. The solution was poured into 500 ml of water and the resultant precipitate was filtered off, dried and chromatographed over silicagel to give 1.7 g of the title compound, m. p. 220―221 °C.

Example 3 2-Cyano-3-(6'-methylergoline-8'β)-N-phenylpropionamide

(I: R1 = anilino, R3 = CN, R4 = CH3, R2 = R5 = R6 = R7 = H)

Operating as in example 2, but employing sodium cyanoacetanilide, 2-cyano-3-(6-methylergoline-8β)-N-phenylpropionamide, m. p. 180-181 °C, was obtained in 60% yield.

Example 4 2-Cyano-3-16'-methylergoline-8'β)-N-propionyl-(N'-methyl)-piperazine

(I: R1 = 4-methyl-1-piperazinyl, R3 = CN, R4 = CH3, R2 = R5 = R6 = R7 = H)

Operating as in example 2, but employing sodium cyanoacetyl-N-methyl-piperazine, the title compound, m. p. 206-207°C, was obtained in 60 % yield.

Example 5 2-Cyano-3-(6'-methylergoline-8'β)-N-ethylpropionamide

(I: R1 = CH3CH2NH, R3 = CN, R4 = CH3, R2 = R5 = R6 = R7 = H)

Operating as in example 2, but employing sodium N-ethylcyanoacetamide, the title compound, m. p. 225-226°C, was obtained in 65% yield.

Example 6 2-Cyano-3-(6'-methylergoline-8'β)-N-benzylpropionamide

(I: R1 = C6H5CH2NH, R3 = CN. R4 = CH3, R2 = R5 = R6 = R7 = H)

Operating as in example 2, but employing sodium N-benzylcyanoacetamide, the title compound, m. p. 233-234°C, was obtained in 75% yield.

Example 7 2-Cyano-3-(6'-methylergoline-8'β)-N-propionylpiperidine

(I: R1 = piperidino, R3 = CN, R4 = CH3, R2 = R5 = R6 = R7 = H)

Operating as in example 2, but employing sodium cyanoacetylpiperidine, the title compound, m. p. 252-253°C, was obtained in 77% yield.

Example 8 2-Cyano-3-(6'-methylergoline-8'β)-propionamide (355/1057)

(I: R1 = NH2, R3 - CN, R4 = CH3, R2 = R5 = R6 = R7 = H)

Operating as in example 2, but employing sodium cyanoacetamide, the title compound, m. p. 248-250°C, was obtained in 45% yield.

Example 9 2-Cyano-3-(6'-ethylergoline-8'β)-N-propionamide

(I: R, = NH2, R3 = CN, R4 = C2H5, R2 = R5 = R6 = R7 = H)

Operating as in example 8, but employing 6-ethyl-8β-tosyloxymethylergoline, the title compound was obtained in 42% yield, m. p. 243-245°C.

Example 10 2-Cyano-3-(6'-allylergoline-8'β)-propionamide

(I: R, = NH2, R3 = CN, R4 = allyl, R2 = R5 = R6 = R7 = H)

Operating as in example 8, but employing 6-allyl-8β-tosyloxymethylergoline, the title compound was obtained in 40% yield.

Example 11 2-Cyano-3-(6'-methylergoline-8'β)-N-propionylpyrrolidine

(I: R, = 1-pyrrolidinyl, R3 = CN, R4 = CH3, R2 = Rs = R6 = R7 = H)

Operating as in example 2, but employing sodium cyanoacetylpyrrolidine, the title compound, m. p. 219―220°C, was obtained in 68% yield.

Example 12 2-Cyano-3-(1',6'-dimethylergoline-8'β)-propionamide

(I: R1 = NH2, R3 = CN, R4 = R7 = CH3, R2 = R5 = R6 = H)

Operating as in example 8, but employing 1,6-dimethyl-8β-tosyloxymethylergoline, the title compound, m. p. 196-197°C, was obtained in 80% yield.

Example 13 2-Cyano-3-(6'-methyl-10'-methoxyergoline-8'β)-propionamide

(I: R1 = NH2, R3 = CN, R4 = CH3, R5 = CH3O, R2 = R6 = R7 = H)

Operating as in example 8, but employing 6-methyl-10-methoxy-8β-tosyloxymethylergoline, the title compound, m. p. 207-208°C, was obtained in 45% yield.

Example 14 2-Cyano-3-(1',6'-dimethyl-10'-methoxyergoline-8'β)-propionamide

(I: R1 = NH2, R3 = CN, R4 = R7 = CH3' R5 = CH3O, R2 = R6 = H)

Operating as in example 8, but employing 1,6-dimethyl-10-methoxy-8β-tosyloxymethylergoline, the title compound, was obtained in 81% yield.

Example 15 2-Cyano-3-(2'-bromo-6'-methylergoline-8'β)-propionamide

(I: R1 = NH2, R3=CN, R4=CH3, R6=Br, R2 = R5 = R7 = H)

Operating as in example 8, but employing 2-bromo-6-methyl-8β-tosyloxymethylergoline, the title compound, m. p. 171-173°C, was obtained in 41% yield.

Example 16 2-Acetyl-3-(6'-methylergoline-8'β)-propionic acid ethyl ester

(I: R, = OCH2CH3, R3 = CH3CO, R4 = CH3, R2 = R5 = R6 = R7 = H)

Operating as in example 1, but employing sodium ethyl acetoacetate, the title compound, m. p. 178-179°C, was obtained in 70% yield.

Example 17 3-Acetyl-4-(6'-methylergoline-8'β)-butanone

(I: R, = R4 = CH3, R3 = CH3CO, R2 = R5 = R6 = R7 = H)

Operating as in example 1, but employing sodium acetylacetone, the title compound, m. p. 210-212°C, was obtained in 75% yield.

Example 18 2-Cyano-2-ethyl-3-(6'-methylergoline-8'β)-propionamide

(I: R1 = NH2' R2 = C2H5' R3 = CN, R4 = CH3, R5 = R6 = R7 = H)

Operating as in example 8, but employing sodium ethylcyanoacetamide, the title compound, m. p. 217°C, was obtained in 43% yield.

Example 19 2-Cyano-2-phenyl-3-(6'-methylergoline-8'β)-propionamide

(I: R1 = NH2, R2 = C6H5, R3 = CN, R4 = CH3, R5 = R6 = R7 = H)

Operating as in example 8, but employing sodium phenylcyanoacetamide, the title compound, m. p. 232°C, was obtained in 45% yield.

_ Example 20 2-Cyano-3-( 1',6'-dimethylergoline-8'β)-N-ethylpropionamide

Operating as in example 5, but employing 1,6-dimethyl-8β-tosyloxymethylergoline, the title compound, m. p. 194-196°C, was obtained in 60% yield.

Example 21 2-Cyano-3-( 1',6'-dimethylergoline-8'β)-N-propionylpyrrolidine

Operating as in example 11, but employing 1,6-dimethyl-8β-tosyloxymethylergoline, the title compound, m. p. 207-209°C, was obtained in 55% yield.

Example 22 2-Cyano-3-( 1',6'-dimethylergoline-8'β)-N-benzylpropionamide

Operating as in example 6, but employing 1,6-dimethyl-8β-tosyloxymethylergoline, the title compound, m. p. 175-177°C, was obtained in 40% yield.

Example 23 2-Methylsulfonyl-3-(6'-methylergoline-8'β)-propionic acid ethyl ester

Operating as in example 1, but employing sodium ethylmethylsulfonylacetate, the title compound, m. p. 199―201 °C, was obtained in 70% yield.

Example 24 2-Methylsulfonyl-3-(6'-methylergoline-8'β)-N-benzylpropionamide

Operating as in example 2, but employing sodium N-benzyl-methylsulfonylacetamide, the title compound, m. p. 285-287°C, was obtained in 60% yield.

Example 25 2-Methylsulfonyl-3-(6'-methylergoline-8'β)-propionamide

Operating as in example 2, but employing sodium methylsulfonylacetamide, the title compound, m. p. 242-244°C, was obtained in 65% yield.

Example 26 2-Methylsulfonyl-3-(6'-methylergoline-8'β)-N-propionylpyrrolidine

Operating as in example 2, but employing sodium methylsulfonylacetylpyrrolidine, the title compound, m. p. 235-237°C, was obtained in 69% yield.

Example 27 2-Methylsulfonyl-3-16'-methylergoline-8'β)-N-ethylpropionamide

Operating as in example 2, but employing sodium N-ethylmethylsulfonylacetamide, the title compound, m. p. 227-229°C, was obtained in 60% yield.

Example 28 2-Acetyl-3-(6'-methylergoline-8'β)-propionamide

Operating as in example 2, but employing sodium acetylacetamide, the title compound, m. p. 225-227°C, was obtained in 40% yield.

Example 29 2-Cyano-3-(2'-chloro-6'-methylergoline-8'β)-propionamide

Operating as in example 8, but employing 2-chloro-6-methyl-8β-tosyloxymethylergoiine, the title compound, m. p. 245-246°C, was obtained in 45% yield.

 1. A compound of the general formula I wherein R, represents an alkyl or alkoxy group having from 1 to 4 carbon atoms, phenyl, a 5- or 6- membered heterocyclic ring which is preferably saturated, an amino group, a substituted amino group of the formula NHR' (wherein R' represents an alkyl group having from 1 to 4 carbon atoms, a cycloalkyl group, a benzyl group or a phenyl group), or a substituted amino group of the formula NR"R"' (wherein R" and R'" both represent alkyl groups having from 1 to 4 carbon atoms); R2 represents a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms or a phenyl group; R3 represents a fluorine atom, a cyano group, a difluoromethyl, difluorobromomethyl and trifluoromethyl group, a methylsulfonyl or a sulfonamido group, an acyl group having from 2 to 5 carbon atoms or a benzoyl group; R4 represents a hydrocarbon group having from 1 to 4 carbon atoms; R5 represents a hydrogen atom or a methoxy group; Rs is hydrogen, a halogen atom or a methyl group; R7 is hydrogen or a methyl group,
and the pharmaceutically acceptable addition salts with organic or inorganic acids thereof. 2. A compound according to claim 1, wherein R, is a methyl group. 3. A compound according to claim 1, wherein R, is the piperidino, 1-pyrrolidinyl, morpholino or 4-methyl-1-piperazinyl group. 4. A compound according to claim 1,2 or 3, wherein R3 is selected from the group consisting of a fluorine atom, difluoromethyl, difluorobromomethyl and a trifluoromethyl group. 5. As a compound according to claim 1 2-Cyano-3-(6'-methylergolin-8'-beta)-n-ethylpropionamide. 6. As a compound according to claim 1 2-Cyano-3-(6'-methylergolin-8'-beta)-n-benzylpropion- amide. 7. As a compound according to claim 1 2-Cyano-3-(6'-methylergolin-8'-beta)-propionamide. 8. As a compound according to claim 1 2-Cyano-3-(6'-methylergolin-8'-beta)-n-propionyl- pyrrolidine. 9. As a compound according to claim 1 2-Cyano-3-(2'-bromo-6'-methylergolin-8'-beta)-propionamide. 10. A process for the preparation of a compound of general formula I, as defined in claims 1 to 4, which comprises condensing a suitable intermediate of formula II: wherein R4, R5, R6 and R7 have the meanings given in claim 1, with an alkaline salt of a compound of formula III: wherein R1, R2, R3 have the meanings already given in claim 1, and, if desired, adding organic or inorganic acid to obtain the addition salt. 11. A process according to claim 10 wherein the condensation is carried out in a polar aprotic solvent. 12. A process according to claim 11 wherein the polar aprotic solvent is dimethylsulfoxide or dimethylformamide. 13. A process according to claim 11, wherein the condensation is carried out in the presence of sodium iodide, and at a temperature of 50-100°C for 2 to 10 hours, whereafter the resulting raw product is purified by chromatography on silicagel. 14. A therapeutical composition containing at least one compound according to claims 1 to 9 as active ingredient along with usual pharmaceutically acceptable additives. 1. Composé de formule générale I: dans laquelle R, représente un groupe alkyle ou alcoxy ayant de 1 à 4 atomes de carbone, phényle, un noyau hétérocyclique à 5 ou 6 chaînons qui est de préférence saturé, un groupe amino, un groupe amino substitué de formule NHR' (où R' représente un groupe alkyle ayant de 1 à 4 atomes de carbone, un groupe cycloalkyle, un groupe benzyle ou un groupe phényie) ou un groupe amino substitué de formule NR"R"' (où R" et R"' représentent chacùn des groupes alkyle ayant de 1 à 4 atomes de carbone); R2 représente un atome d'hydrogène, un groupe alkyle ayant de 1 à 4 atomes de carbone ou un groupe phényle; R3 représente un atome de fluor, un groupe cyano, un groupe difluorométhyle, difluorobromométhyle et trifluorométhyle, un groupe méthylsulfonyle ou sulfonamido, un groupe acyle ayant de 2 à 5 atomes de carbone ou un groupe benzoyle; R4 représente un groupe hydrocarboné ayant de 1 à 4 atomes de carbone; R5 représente un atome d'hydrogène ou un groupe méthoxy; R6 est un atome d'hydrogène, un atome d'halogène ou un groupe méthyle; R7 est hydrogène ou un groupe methyle;
et les sels d'addition pharmaceutiquement acceptables de ce composé avec des acides organiques ou minéraux. 2. Composé selon la revendication 1, où R1 est un groupe méthyle. 3. Composé selon la revendication 1 ou 2, où R, est un groupe pipéridino, 1-pyrrolidinyle, morpholino ou 4-méthyl-1-pipérazinyle. 4. Composé selon les revendications 1,2 ou 3 où R3 est choisi d'un groupe formé par un atome de fluor, un groupe difluorométhyle, difluorobromométhyle et trifluorométhyle. 5. Le composé selon la revendication 1 est le 2-cyano-3-(6'-méthylergoline-8'-bêta)-n-éthyl- propionamide. 6. Le composé selon la revendication 1 est le 2-cyano-3-(6'-méthylergoline-8'-bêta)-n-benzyl- propionamide. 7. Le composé selon la revendication 1 est le 2-cyano-3-(6-méthylergoline-8'-bâta)-propion- amide. 8. Le composé selon la revendication 1 est le 2-cyano-3-(6'-méthylergoline-8'-bêta)-n-propionyl- pyrrolidine. 9. Le composé selon la revendication 1 est le 2-cyano-3-(2'-bromo-6'-méthylergoline-8'-bêta)-propionamide. 10. Procédé de préparation d'un composé de formule générale I tel que défini dans les revendications 1 à 4, comprenant la condensation d'un intermédiaire approprié de formule II: dans laquelle R4, R5, R6 et R7 ont les significations indiquées dans la revendication 1, avec un sel alcalin d'un composé de formule III: dans laquelle R1 R2, R3 ont les significations indiquées dans la revendication 1, et si on le désire, addition d'un acide organique ou minéral pour obtenir le sel d'addition. 11. Procédé selon la revendication 10 lorsque la condensation est mise en oeuvre dans un solvant polaire neutre (qui ne cède ni ne fixe de proton). 12. Procédé selon la revendication 11 lorsque le solvant polaire neutre est le diméthylsulfoxyde ou le diméthylformamide. 13. Procédé selon la revendication 11, lorsque la condensation est mise en oeuvre en présence d' iodure de sodium et a une température de 50―100°C pendant 2 à 10 heures, le produit brut résultant étant purifié ensuite par chromatographie sur gel de silice. 14. Composition thérapeutique contenant au moins un composé selon les revendications 1 à 9, en tant qu'ingrédient actif, ensemble avec des additifs usuels pharmaceutiquement acceptables. 1. Eine Verbindung der allgemeinen Formel (I) worin R, eine Alkyl- oder Alkoxygruppe mit 1 bis 4 Kohlenstoffatomen, Phenyl, einen 5- oder 6- gliedrigen heterozyklishen Ring, der vorzugsweise gesättigt ist, eine Aminogruppe, eine substituierte Aminogruppe der Formel NHR' (worin R' eine Alkylgruppe mit 1 bis 4 Kohlenstoffatomen, eine Cycloalkylgruppe, eine Benzylgruppe oder eine Phenylgruppe bedeutet) oder eine substituierte Aminogruppe der Formel NR"R"' (worin R" und R'" beide Alkylgruppen mit 1 bis 4 Kohlenstoffatomen bedeuten); R2 ein Wasserstoffatom, eine Alkylgruppe mit 1 bis 4 Kohlenstoffatomen oder eine Phenylgruppe; R3 ein Fluoratom, ein Cyanogruppe, eine Difluormethyl-, eine Difluorbromomethyl- und Trifluormethylgruppe, eine Methylsulfonyl- oder eine Sulfonamidogruppe,eine Acylgruppe mit 2 bis 5 Kohlenstoffatomen oder eine Benzoylgruppe. R4 eine Kohlenwasserstoffgruppe mit 1 bis 4 Kohlenstoffatomen; R5 ein Wasserstoffatom oder eine Methoxygruppe; R6 ein Wasserstoffatom, ein Halogenatom oder eine Methylgruppe; R7 ein Wasserstoffatom oder eine Methylgruppe
bedeuten, und pharmazeutisch annehmbare Additionssalze mit anorganischen oder organischen Säuren. 2. Verbindung gemäss Anspruch 1, worin R, eine Methylgruppe ist. 3. Verbindung gemäss Anspruch 1, worin R, die Piperidino-, 1-Pyrrolidinyl-, Morpholino- oder 4-Methyl-1-piperazinylgrupe ist. 4. Verbindung gemäss Ansprüchen 1, 2 oder 3, worin R3 ausgewählt ist aus der Gruppe bestehend aus einem Fluoratom, einer Difluoromethyl-, Difluorobromomethyl- und einer Trifluoromethylgruppe. 5. Als Verbindung gemäss Anspruch 1 2-Cyano-3-(6'-methylergolin-8'-beta)-n-ethylpropion- amid. 6. Als Verbindung gemäss Anspruch 1 2-Cyano-3-(6'-methylergolin-8'-beta)-n-benzylpropion- amid. 7. Als Verbindung gemäss Anspruch 1 2-Cyano-3-(6'-methylergolin-8'-beta)-propionamid. 8. Als Verbindung gemäss Anspruch 1 2-Cyano-3-(6'-methylergolin-8'-beta)-n-propionyl- pyrrolidin. 9. Als Verbindung gemäss Anspruch 1 2-Cyano-3-(2'-bromo-6'-methylergolin-8'-beta)-propionamid. 10. Verfahren zur Herstellung einer Verbindung der allgemeinen Formel (I) gemäss Ansprüchen 1 bis 4, dadurch gekennzeichnet, dass manein geeignetes Zwischenprodukt der Formel (II) worin R4, R5, R6 und R7 die in Anspruch 1 angegebenen Bedeutungen haben, mit einem Alkalisalz der Verbindung der Formel (III) worin R1, R2 und R3 die vorher in Anspruch 1 angegebenen Bedeutungen haben, kondensiert und gewünschtenfalls eine organische oder anorganische Säure zur Herstellung des Additionssalzes zugibt. 11. Verfahren gemäss Anspruch 10, dadurch gekennzeichnet, dass die Kondensation in einem polaren aprotischen Lösungsmittel durchgeführt wird. 12. Verfahren gemäss Anspruch 11, dadurch gekennzeichnet, dass das polare aprotische Lösungsmittel Dimethylsulfoxid oder Dimethylformamid ist. 13. Verfahren gemäss Anspruch 11, dadurch gekennzeichnet, dass die Kondensation in Gegenwart von Natriumjodid und bei einer Temperatur von 50 bis 100°C während 2 bis 10 Stunden durchgeführt wird, worauf man das erhaltene Rohprodukt dann chromatografisch über Kieselgel reinigt. 14. Therapeutischea Zusammensetzung, enthaltend wenigstens eine Verbindung gemäss Ansprüchen 1 bis 9 als aktiven Bestandteil zusammen mit üblichen pharmazeutisch annehmbaren Additiven.